ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS · Intestinal obstruction and ileus/subileus In very...

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT Renagel 400 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 400 mg sevelamer hydrochloride. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet) The off-white, oval tablets are imprinted with “Renagel 400” on one side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis. Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to control the development of renal bone disease. 4.2 Posology and method of administration Posology Starting dose The recommended starting dose of sevelamer hydrochloride is 2.4 g, 3.6 g or 4.8 g per day based on clinical needs and serum phosphorus level. Renagel must be taken three times per day with meals.

Serum phosphate level in patients not on phosphate binders

Starting dose of Renagel 400 mg tablets

1.76 – 2.42 mmol/L (5.5-7.5 mg/dl) 2 tablets, 3 times per day 2.42- 2.91 mmol/L (7.5-9 mg/dl) 3 tablets, 3 times per day

> 2.91 mmol/L 4 tablets, 3 times per day For patients previously on phosphate binders, Renagel should be given on a gram for gram basis with monitoring of serum phosphorus levels to ensure optimal daily doses. Titration and maintenance Serum phosphate levels should be closely monitored and the dose of sevelamer hydrochloride titrated by 0.4 g or 0.8 g three times per day (1.2 g/day or 2.4 g/day) increments with the goal of lowering serum phosphate to 1.76 mmol/L (5.5mg/dl) or less. Serum phosphate should be tested every two to three weeks until a stable serum phosphate level is reached and on a regular basis thereafter. The dose range may vary between 1 and 10 tablets per meal. The average actual daily dose used in the chronic phase of a one year clinical study was 7 grams of sevelamer. Paediatric population The safety and efficacy of this product have not been established in patients below the age of 18 years.

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Renal impairment The safety and efficacy of this product have not been established in predialysis patients. Method of administration For oral use. Patients should take Renagel with meals and adhere to their prescribed diets. The tablets must be swallowed whole. Do not crush, chew or break into pieces prior to administration. 4.3 Contraindications • Hypersensitivity to sevelamer or to any of the excipients listed in section 6.1. • Hypophosphataemia • Bowel obstruction. 4.4 Special warnings and precautions for use Efficacy and safety of Renagel has not been studied in patients with:

• swallowing disorders • active inflammatory bowel disease • gastrointestinal motility disorders including untreated or severe gastroparesis, diverticulosis

retention of gastric contents and abnormal or irregular bowel motion • patients with a history of major gastrointestinal surgery

Therefore caution should be exercised when Renagel is used in patients with these disorders. Intestinal obstruction and ileus/subileus In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with sevelamer hydrochloride. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with sevelamer hydrochloride. Renagel treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms. Fat-soluble vitamins Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fat-soluble vitamins contained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of thromboplastin time should be considered and the vitamins should be supplemented if necessary. Additional monitoring of vitamins and folic acid is recommended in patients receiving peritoneal dialysis, since in the clinical study, vitamin A, D, E and K levels were not measured in these patients. Folate deficiency There is at present insufficient data to exclude the possibility of folate deficiency during long term Renagel treatment. Hypocalcaemia/hypercalcaemia Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does not contain calcium. Serum calcium levels should be monitored as is done in normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia. Metabolic acidosis Patients with chronic renal failure are predisposed to developing metabolic acidosis. Worsening of acidosis has been reported upon switching from other phosphate binders to sevelamer in a number of studies where lower bicarbonate levels in the sevelamer-treated patients compared to patients treated with calcium-based binders were observed. Closer monitoring of serum bicarbonate levels is therefore recommended.

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Peritonitis Patients receiving dialysis are subject to certain risks for infection specific to the dialysis modality. Peritonitis is a known complication in patients receiving peritoneal dialysis (PD) and in a clinical study with Renagel, a number of peritonitis cases were reported. Therefore, patients on PD should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. Swallowing and choking difficulties Uncommon reports of difficulty swallowing the Renagel tablet have been reported. Many of these cases involved patients with co-morbid conditions including swallowing disorders or oesophageal abnormalities. Caution should be exercised when Renagel is used in patients with difficulty swallowing. Hypothyroidism Closer monitoring of patients with hypothyroidism co-administered with sevelamer hydrochloride and levothyroxine is recommended (see section 4.5). Long term chronic treatment As data on the chronic use of sevelamer for over one year are not yet available, potential absorption and accumulation of sevelamer during long-term chronic treatment cannot be totally excluded (see section 5.2). Hyperparathyroidism Renagel alone is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to lower the intact parathyroid hormone (iPTH) levels. Serum chloride Serum chloride may increase during Renagel treatment as chloride may be exchanged for phosphorus in the intestinal lumen. Although no clinically significant serum chloride increase has been observed in the clinical studies, serum chloride should be monitored as is done in the routine follow-up of a dialysis patient. One gram of Renagel contains approximately 180 mg (5.1 mEq) chloride. Inflammatory Gastrointestinal Disorders Cases of serious inflammatory disorders of different parts of the gastrointestinal tract (including serious complications such as haemorrhage, perforation, ulceration, necrosis, colitis and colonic/caecal mass) associated with the presence of sevelamer crystals have been reported (see section 4.8). Inflammatory disorders may resolve upon sevelamer discontinuation. Sevelamer hydrochloride treatment should be re-evaluated in patients who develop severe gastrointestinal symptoms. 4.5 Interaction with other medicinal products and other forms of interaction Dialysis Interaction studies have not been conducted in patients on dialysis. Ciprofloxacin In interaction studies in healthy volunteers, sevelamer hydrochloride decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with Renagel in a single dose study. Consequently, Renagel should not be taken simultaneously with ciprofloxacin. Anti-arrhythmics and anti-seizure medicinal products Patients taking anti-arrhythmic medicinal products for the control of arrhythmias and anti-seizure medicinal products for the control of seizure disorders were excluded from clinical trials. Caution

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should be exercised when prescribing sevelamer hydrochloride to patients also taking these medicinal products. Levothyroxine During post marketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medicinal products. Ciclosporin, mycophenolate mofetil and tacrolimus in transplant patients Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when coadministered with sevelamer hydrochloride without any clinical consequences (i.e graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during the use of combination and after its withdrawal. Digoxin, warfarin, enalapril or metoprolol In interaction studies in healthy volunteers, Renagel had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol. Proton pump inhibitors During post-marketing experience, very rare cases of increased phosphate levels have been reported in patients taking proton pump inhibitors co-administered with sevelamer hydrochloride. Bioavailability Renagel is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product where a reduction in the bioavailability could have a clinically significant effect on safety or efficacy, the medicinal product should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels. 4.6 Fertility, pregnancy and lactation Pregnancy The safety of sevelamer hydrochloride has not been established in pregnant women. In animal studies there was no evidence that sevelamer induced embryo-foetal toxicity. Renagel should only be given to pregnant women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the foetus (see section 5.3). Breast-feeding The safety of sevelamer hydrochloride has not been established in breast-feeding women. Renagel should only be given to breast-feeding women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the infant (see section 5.3). Fertility There are no data from the effect of sevelamer on fertility in humans. Studies in animals have shown that sevelamer did not impair fertility in male or female rats at exposures at a human equivalent dose 2 times the maximum clinical trial dose of 13 g/day, based on a comparison of relative body surface area. 4.7 Effects on ability to drive and use machines Sevelamer has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile

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The most frequently occurring (≥5% of patients) adverse reactions were all in the gastrointestinal disorders system organ class. Tabulated list of adverse reactions Parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54 weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks were conducted. Adverse reactions from these studies (299 patients), from uncontrolled clinical trials (384 patients), and that were spontaneously reported from post-marketing experience are listed by frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

MedDRA System Organ Class

Very Common

Common Uncommon Very Rare Not known

Immune system disorders

Hypersensitivity*

Metabolism and nutrition disorders

Acidosis, increased serum chloride levels

Gastrointestinal disorders

Nausea, vomiting

Diarrhoea, dyspepsia, flatulence, upper abdominal pain, constipation

Abdominal pain, intestinal obstruction, ileus/subileus, diverticulitis, intestinal perforation1, gastrointestinal hemorrhage*1, intestinal ulceration*1, gastrointestinal necrosis*1, colitis*1, intestinal mass*1

Skin and subcutaneous tissue disorders

Pruritus, rash

Investigations Crystal deposit intestine*1

*post-marketing experience 1 See inflammatory gastrointestinal disorders warning in section 4.4 Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Renagel has been given to normal healthy volunteers in doses up to 14 grams, the equivalent of thirty five 400 mg tablets per day for eight days with no undesirable effects.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc

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5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Treatment of hyperphosphatemia. ATC code: V03AE02. Renagel contains sevelamer, a non-absorbed phosphate binding poly (allylamine hydrochloride) polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines become partially protonated in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract, sevelamer lowers the phosphate concentration in the serum. In clinical trials, sevelamer has been shown to be effective in reducing serum phosphorus in patients receiving haemodialysis or peritoneal dialysis. Sevelamer decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone, probably because the product itself does not contain calcium. The effects on phosphate and calcium were proven to be maintained throughout a study with one year follow-up. Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. In clinical trials mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks is maintained with long-term treatment. Triglycerides, HDL cholesterol and albumin did not change. In the clinical studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on serum intact parathyroid hormone (iPTH). In the 12 week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to lower the iPTH levels. In a clinical trial of one-year duration, Renagel had no adverse effect on bone turnover or mineralisation compared to calcium carbonate. 5.2 Pharmacokinetic properties Renagel is not absorbed from the gastrointestinal tract according to a single dose pharmacokinetic study in healthy volunteers. Pharmacokinetic studies have not been carried out in renal failure patients (see section 4.4). 5.3 Preclinical safety data In preclinical studies in rats and dogs, Renagel at a dose of 10 times the maximum human doses reduced absorption of fat soluble vitamins D, E and K, and folic acid. In a study in rats, administering sevelamer in 15-30 x the human dose, an increase in serum copper was detected. This was not confirmed in a dog study or in clinical trials. Currently, no formal carcinogenicity data are available. However, in vitro and in vivo studies have indicated that Renagel does not have genotoxic potential. Also the medicinal product is not absorbed in the gastrointestinal tract.

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In reproduction studies there was no evidence that sevelamer induced embryolethality, foetotoxicity or teratogenicity at the doses tested (up to 1 g/kg/day in rabbits and up to 4.5 g/kg/day in rats). Deficits in skeletal ossification were observed in several locations in fetuses of female rats dosed with sevelamer at 8-20 times the maximum human dose of 200 mg/kg. The effects may be secondary to vitamin D and/or vitamin K depletion at these high doses. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Silica, colloidal anhydrous Stearic acid Film-coating: Hypromellose (E464) Diacetylated monoglycerides Printing ink: Iron oxide black (E172) Propylene glycol Hypromellose (E464) 6.2 Incompatibilities Not applicable 6.3 Shelf-life 2 years. 6.4 Special precautions for storage Do not store above 25ºC. Keep the bottle tightly closed in order to protect from moisture. 6.5 Nature and contents of container HDPE bottles, with a child resistant polypropylene closure and a foil induction seal. Package sizes are: 1 bottle of 360 film-coated tablets multipacks containing 720 film-coated tablets (2 bottles of 360 tablets) multipacks containing 1080 film-coated tablets (3 bottles of 360 tablets) Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER

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Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, the Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/99/123/005 1 bottle of 360 film-coated tablets EU/1/99/123/006 multipacks containing 720 film-coated tablets (2 bottles of 360 tablets) EU/1/99/123/007 multipacks containing 1080 film-coated tablets (3 bottles of 360 tablets) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 28 January 2000 Date of latest renewal: 28 January 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.

http://www.ema.europa.eu/

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1. NAME OF THE MEDICINAL PRODUCT Renagel 800 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 800 mg sevelamer hydrochloride. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet) The off-white, oval tablets are imprinted with “Renagel 800” on one side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis. Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to control the development of renal bone disease. 4.2 Posology and method of administration Posology Starting dose The recommended starting dose of sevelamer hydrochloride is 2.4 g or 4.8 g per day based on clinical needs and serum phosphorus level. Renagel must be taken three times per day with meals.

Serum phosphate level in patients not on phosphate binders

Starting dose of Renagel 800 mg tablets

1.76 – 2.42 mmol/L (5.5-7.5 mg/dl) 1 tablet, 3 times per day > 2.42 mmol/L (>7.5 mg/dl) 2 tablets, 3 times per day

For patients previously on phosphate binders, Renagel should be given on a gram for gram basis with monitoring of serum phosphorus levels to ensure optimal daily doses. Titration and maintenance Serum phosphate levels should be closely monitored and the dose of sevelamer hydrochloride titrated by 0.8 g three times per day (2.4 g/day) increments with the goal of lowering serum phosphate to 1.76 mmol/L (5.5 mg/dl) or less. Serum phosphate should be tested every two to three weeks until a stable serum phosphate level is reached and on a regular basis thereafter. The dose range may vary between 1 and 5 tablets of 800 mg per meal. The average actual daily dose used in the chronic phase of a one year clinical study was 7 grams of sevelamer. Paediatric population The safety and efficacy of this product have not been established in patients below the age of 18 years.

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Renal impairment The safety and efficacy of this product have not been established in predialysis patients. Method of administration For oral use Patients should take Renagel with meals and adhere to their prescribed diets. The tablets must be swallowed whole. Do not crush, chew or break into pieces prior to administration. 4.3 Contraindications • Hypersensitivity to sevelamer or to any of the excipients listed in section 6.1. • Hypophosphataemia • Bowel obstruction. 4.4 Special warnings and precautions for use Efficacy and safety of Renagel has not been studied in patients with:

• swallowing disorders • active inflammatory bowel disease • gastrointestinal motility disorders including untreated or severe gastroparesis, diverticulosis

retention of gastric contents and abnormal or irregular bowel motion • patients with a history of major gastrointestinal surgery

Therefore caution should be exercised when Renagel is used in patients with these disorders. Intestinal obstruction and ileus/subileus In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with sevelamer hydrochloride. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with sevelamer hydrochloride. Renagel treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms. Fat-soluble vitamins Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fat-soluble vitamins contained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of thromboplastin time should be considered and the vitamins should be supplemented if necessary. Additional monitoring of vitamins and folic acid is recommended in patients receiving peritoneal dialysis, since in the clinical study, vitamin A, D, E and K levels were not measured in these patients. Folate deficiency There is at present insufficient data to exclude the possibility of folate deficiency during long term Renagel treatment. Hypocalcaemia/hypercalcaemia Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does not contain calcium. Serum calcium levels should be monitored as is done in normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia. Metabolic acidosis Patients with chronic renal failure are predisposed to developing metabolic acidosis. Worsening of acidosis has been reported upon switching from other phosphate binders to sevelamer in a number of studies where lower bicarbonate levels in the sevelamer-treated patients compared to patients treated with calcium-based binders were observed. Closer monitoring of serum bicarbonate levels is therefore recommended.

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Peritonitis Patients receiving dialysis are subject to certain risks for infection specific to the dialysis modality. Peritonitis is a known complication in patients receiving peritoneal dialysis (PD) and in a clinical study with Renagel, a number of peritonitis cases were reported. Therefore, patients on PD should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. Swallowing and choking difficulties Uncommon reports of difficulty swallowing the Renagel tablet have been reported. Many of these cases involved patients with co-morbid conditions including swallowing disorders or oesophageal abnormalities. Caution should be exercised when Renagel is used in patients with difficulty swallowing. Hypothyroidism Closer monitoring of patients with hypothyroidism co-administered with sevelamer hydrochloride and levothyroxine is recommended (see section 4.5). Long term chronic treatment As data on the chronic use of sevelamer for over one year are not yet available, potential absorption and accumulation of sevelamer during long-term chronic treatment cannot be totally excluded (see section 5.2). Hyperparathyroidism Renagel alone is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to lower the intact parathyroid hormone (iPTH) levels. Serum chloride Serum chloride may increase during Renagel treatment as chloride may be exchanged for phosphorus in the intestinal lumen. Although no clinically significant serum chloride increase has been observed in the clinical studies, serum chloride should be monitored as is done in the routine follow-up of a dialysis patient. One gram of Renagel contains approximately 180 mg (5.1 mEq) chloride. Inflammatory Gastrointestinal Disorders Cases of serious inflammatory disorders of different parts of the gastrointestinal tract (including serious complications such as haemorrhage, perforation, ulceration, necrosis, colitis and colonic/caecal mass) associated with the presence of sevelamer crystals have been reported (see section 4.8). Inflammatory disorders may resolve upon sevelamer discontinuation. Sevelamer hydrochloride treatment should be re-evaluated in patients who develop severe gastrointestinal symptoms. 4.5 Interaction with other medicinal products and other forms of interaction Dialysis Interaction studies have not been conducted in patients on dialysis. Ciprofloxacin In interaction studies in healthy volunteers, sevelamer hydrochloride decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with Renagel in a single dose study. Consequently, Renagel should not be taken simultaneously with ciprofloxacin. Anti-arrhythmics and anti-seizure medicinal products Patients taking anti-arrhythmic medicinal products for the control of arrhythmias and anti-seizure medicinal products for the control of seizure disorders were excluded from clinical trials. Caution should be exercised when prescribing sevelamer hydrochloride to patients also taking these medicinal products.

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Levothyroxine During post marketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medicinal products. Ciclosporin, mycophenolate mofetil and tacrolimus in transplant patients Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when coadministered with sevelamer hydrochloride without any clinical consequences (i.e graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during the use of combination and after its withdrawal. Digoxin, warfarin, enalapril or metoprolol In interaction studies in healthy volunteers, Renagel had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol. Proton pump inhibitors During post-marketing experience, very rare cases of increased phosphate levels have been reported in patients taking proton pump inhibitors co-administered with sevelamer hydrochloride. Bioavailability Renagel is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product where a reduction in the bioavailability could have a clinically significant effect on safety or efficacy, the medicinal product should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels. 4.6 Fertility, pregnancy and lactation Pregnancy The safety of sevelamer hydrochloride has not been established in pregnant women. In animal studies there was no evidence that sevelamer induced embryo-foetal toxicity. Renagel should only be given to pregnant women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the foetus (see section 5.3). Breast-feeding The safety of sevelamer hydrochloride has not been established in breast-feeding women. Renagel should only be given to breast-feeding women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the infant (see section 5.3). Fertility There are no data from the effect of sevelamer on fertility in humans. Studies in animals have shown that sevelamer did not impair fertility in male or female rats at exposures at a human equivalent dose 2 times the maximum clinical trial dose of 13 g/day, based on a comparison of relative body surface area. 4.7 Effects on ability to drive and use machines Sevelamer has no or negligible influence on the ability to drive and use machines.

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4.8 Undesirable effects Summary of the safety profile The most frequently occurring (≥5% of patients) adverse reactions were all in the gastrointestinal disorders system organ class. Tabulated list of adverse reactions In parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54 weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks were conducted. Adverse reactions from these studies (299 patients), from uncontrolled clinical trials (384 patients), and that were spontaneously reported from post-marketing experience are listed by frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated form the available data).

MedDRA System Organ Class

Very Common

Common Uncommon Very Rare Not known

Immune system disorders

Hypersensitivity*

Metabolism and nutrition disorders

Acidosis, increased serum chloride levels

Gastrointestinal disorders

Nausea, vomiting

Diarrhoea, dyspepsia, flatulence, upper abdominal pain, constipation

Abdominal pain, intestinal obstruction, ileus/subileus, diverticulitis, intestinal perforation1, gastrointestinal hemorrhage*1, intestinal ulceration*1, gastrointestinal necrosis*1, colitis*1, intestinal mass*1

Skin and subcutaneous tissue disorders

Pruritus, rash

Investigations Crystal deposit intestine*1

*post-marketing experience 1 See inflammatory gastrointestinal disorders warning in section 4.4 Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.


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4.9 Overdose Renagel has been given to normal healthy volunteers in doses up to 14 grams, the equivalent of seventeen 800 mg tablets per day for eight days with no undesirable effects. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Treatment of hyperphosphatemia. ATC code: V03AE02. Renagel contains sevelamer, a non-absorbed phosphate binding poly (allylamine hydrochloride) polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines become partially protonated in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract, sevelamer lowers the phosphate concentration in the serum. In clinical trials, sevelamer has been shown to be effective in reducing serum phosphorus in patients receiving haemodialysis or peritoneal dialysis. Sevelamer decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone, probably because the product itself does not contain calcium. The effects on phosphate and calcium were proven to be maintained throughout a study with one year follow-up. Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. In clinical trials mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks is maintained with long-term treatment. Triglycerides, HDL cholesterol and albumin did not change. In the clinical studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on serum intact parathyroid hormone (iPTH). In the 12 week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to lower the iPTH levels. In a clinical trial of one-year duration, Renagel had no adverse effect on bone turnover or mineralisation compared to calcium carbonate. 5.2 Pharmacokinetic properties Renagel is not absorbed from the gastrointestinal tract according to a single dose pharmacokinetic study in healthy volunteers. Pharmacokinetic studies have not been carried out in renal failure patients (see section 4.4). 5.3 Preclinical safety data In preclinical studies in rats and dogs, Renagel at a dose of 10 times the maximum human doses reduced absorption of fat soluble vitamins D, E and K, and folic acid. In a study in rats, administering sevelamer in 15-30 x the human dose, an increase in serum copper was detected. This was not confirmed in a dog study or in clinical trials.

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Currently, no formal carcinogenicity data are available. However, in vitro and in vivo studies have indicated that Renagel does not have genotoxic potential. Also the medicinal product is not absorbed in the gastrointestinal tract. In reproduction studies there was no evidence that sevelamer induced embryolethality, foetotoxicity or teratogenicity at the doses tested (up to 1 g/kg/day in rabbits and up to 4.5 g/kg/day in rats). Deficits in skeletal ossification were observed in several locations in fetuses of female rats dosed with sevelamer at 8-20 times the maximum human dose of 200 mg/kg. The effects may be secondary to vitamin D and/or vitamin K depletion at these high doses. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Silica, colloidal anhydrous Stearic acid Film-coating: Hypromellose (E464) Diacetylated monoglycerides Printing ink: Iron oxide black (E172) Propylene glycol Hypromellose (E464) 6.2 Incompatibilities Not applicable 6.3 Shelf-life 3 years 6.4 Special precautions for storage Do not store above 25ºC. Keep the bottle tightly closed in order to protect from moisture. 6.5 Nature and contents of container HDPE bottles, with a child resistant polypropylene closure and a foil induction seal. Package sizes are: 1 bottle of 100 film-coated tablets 1 bottle of 180 film-coated tablets multipacks containing 180 film-coated tablets (6 bottles of 30 tablets) multipacks containing 360 film-coated tablets (2 bottles of 180 tablets) multipacks containing 540 film-coated tablets (3 bottles of 180 tablets) Not all pack sizes may be marketed.

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6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, the Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/99/123/008 1 bottle of 180 film-coated tablets EU/1/99/123/009 multipacks containing 360 film-coated tablets (2 bottles of 180 tablets) EU/1/99/123/010 multipacks containing 540 film-coated tablets (3 bottles of 180 tablets) EU/1/99/123/011 1 bottle of 100 film-coated tablets EU/1/99/123/012 1 bottle of 180 film-coated tablets without outer carton EU/1/99/123/013 multipacks containing 180 film-coated tablets (6 bottles of 30 tablets) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 28 January 2000 Date of latest renewal: 28 January 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.


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ANNEX II

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

19

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Genzyme Limited, 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom Genzyme Ireland Ltd., IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION • Periodic Safety Update Reports The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:

• At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information

being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

20

ANNEX III

LABELLING AND PACKAGE LEAFLET

21

A. LABELLING

22

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON – 1 BOTTLE OF 360 TABLETS 400 mg

1. NAME OF THE MEDICINAL PRODUCT Renagel 400 mg film-coated tablets sevelamer hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 400 mg sevelamer hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS 360 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION Tablets must be swallowed whole. Do not chew. Read the package leaflet before use. For oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE EXP

9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Keep the bottle tightly closed in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

23

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Genzyme Europe B.V. Paasheuvelweg 25 1105 BP Amsterdam The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) EU/1/99/123/005

13. BATCH NUMBER Batch

14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Renagel 400 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN:

24

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON with the Blue Box – MULTIPACK OF 720 (2 BOTTLES OF 360) TABLETS 400 mg OUTER CARTON with the Blue Box – MULTIPACK OF 1080 (3 BOTTLES OF 360) TABLETS 400 mg




4. PHARMACEUTICAL FORM AND CONTENTS Multipack: 720 (2 bottles of 360) film-coated tablets. Multipack: 1080 (3 bottles of 360) film-coated tablets.





8. EXPIRY DATE EXP


25

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE


12. MARKETING AUTHORISATION NUMBER(S) EU/1/99/123/006 multipacks containing 720 film-coated tablets (2 bottles of 360 tablets) EU/1/99/123/007 multipacks containing 1080 film-coated tablets (3 bottles of 360 tablets)




26

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING LABEL - BOTTLE OF 360 TABLETS 400 mg




4. PHARMACEUTICAL FORM AND CONTENTS 360 film-coated tablets





8. EXPIRY DATE EXP



27





15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Renagel 400 mg

28

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING LABEL without Blue Box - BOTTLE OF 360 TABLETS 400 mg (MULTIPACK PRESENTATION)




4. PHARMACEUTICAL FORM AND CONTENTS 360 film-coated tablets. Component of a multipack, can’t be sold separately.





8. EXPIRY DATE EXP



29

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Genzyme Europe B.V. Paasheuvelweg 25 1105 BP Amsterdam The Netherlands





30

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON with Blue Box – MULTIPACK OF 180 (6 BOTTLES OF 30) TABLETS 800 mg




4. PHARMACEUTICAL FORM AND CONTENTS Multipack: 180 (6 bottles of 30) film-coated tablets





8. EXPIRY DATE EXP



31







32

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON – 1 BOTTLE OF 100 TABLETS 800 mg OUTER CARTON – 1 BOTTLE OF 180 TABLETS 800 mg




4. PHARMACEUTICAL FORM AND CONTENTS 100 film-coated tablets 180 film-coated tablets





8. EXPIRY DATE EXP


33




12. MARKETING AUTHORISATION NUMBER(S) EU/1/99/123/011 1 bottle of 100 film-coated tablets EU/1/99/123/008 1 bottle of 180 film-coated tablets




34

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON with Blue Box - MULTIPACK OF 360 (2 BOTTLES OF 180) TABLETS 800 mg OUTER CARTON with Blue Box - MULTIPACK OF 540 (3 BOTTLES OF 180) TABLETS 800 mg




4. PHARMACEUTICAL FORM AND CONTENTS Multipack: 360 (2 bottles of 180) film-coated tablets Multipack: 540 (3 bottles of 180) film-coated tablets.





8. EXPIRY DATE EXP


35








36

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING LABEL without Blue Box - BOTTLE OF 30 TABLETS 800 mg (MULTIPACK PRESENTATION)









8. EXPIRY DATE EXP



37







38

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING LABEL – BOTTLE OF 100 TABLETS 800 mg LABEL - BOTTLE OF 180 TABLETS 800 mg WITH OUTER CARTON LABEL with Blue Box – 1 BOTTLE OF 180 TABLETS 800 mg WITHOUT OUTER CARTON




4. PHARMACEUTICAL FORM AND CONTENTS 100 film-coated tablets 180 film-coated tablets





8. EXPIRY DATE EXP


39



12. MARKETING AUTHORISATION NUMBER(S) EU/1/99/123/011 1 bottle of 100 film-coated tablets EU/1/99/123/008 1 bottle of 180 film-coated tablets with outer carton EU/1/99/123/012 1 bottle of 180 film-coated tablets without outer carton




40

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING LABEL without Blue Box – BOTTLE OF 180 TABLETS 800 mg WITH OUTER CARTON (MULTIPACK PRESENTATION)









8. EXPIRY DATE EXP



41







42

B. PACKAGE LEAFLET

43

Package leaflet: Information for the user

Renagel 400 mg film-coated tablets sevelamer hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even

if their signs of illness are the same as yours. - If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4. What is in this leaflet 1. What Renagel is and what it is used for 2. What you need to know before you take Renagel 3. How to take Renagel 4. Possible side effects 5. How to store Renagel 6. Contents of the pack and other information 1. What Renagel is and what it is used for Renagel contains sevelamer as the active ingredient. It binds phosphate from food in the digestive tract and so reduces serum phosphate levels in the blood. Renagel is used to control the levels of phosphate in the blood of adult kidney failure patients on haemodialysis or peritoneal dialysis treatment. Adult patients whose kidneys have failed and who are undergoing haemodialysis or peritoneal dialysis are not able to control the level of serum phosphate in their blood. The amount of phosphate then rises (your doctor will call this hyperphosphataemia). Increased levels of serum phosphorus can lead to hard deposits in your body called calcification. These deposits can stiffen your blood vessels and make it harder for blood to be pumped around the body. Increased serum phosphorus can also lead to itchy skin, red eyes, bone pain and fractures. Renagel may be used with other medicines which include calcium or vitamin D supplements to control the development of renal bone disease. 2. What you need to know before you take Renagel Do not take Renagel: • if you have low levels of phosphate in your blood (your doctor will check this for you). • if you have bowel obstruction. • if you are allergic to sevelamer or to any of the other ingredients of this medicine (listed in section

6).

Warnings and precautions Talk to your doctor before taking Renagel if any of the following applies to you:

• if you are not on dialysis • if you have swallowing problems • if you have problems with motility (movement) in your stomach and bowel • if you have symptoms of delayed emptying of stomach contents such as feeling of fullness,

nausea and/or vomiting

44

• if you have prolonged diarrhoea or pain in the abdomen (symptoms of active inflammatory bowel disease)

• if you have undergone major surgery on your stomach or bowel • if you have serious inflammatory bowel disease.

Additional treatments: Due to either your kidney condition or your dialysis treatment you may:

• develop a low or high level of calcium in your blood. Since Renagel does not contain calcium your doctor might prescribe additional calcium tablets.

• have a low amount of vitamin D in your blood. Therefore, your doctor may monitor the levels of vitamin D in your blood and prescribe additional vitamin D as necessary. If you do not take multivitamin supplements you may also develop low levels of vitamins A, E, K and folic acid in your blood and therefore your doctor may monitor these levels and prescribe supplemental vitamins as necessary.

Changing treatment: When you switch from another phosphate binder to Renagel, your doctor might consider monitoring the levels of bicarbonate in your blood more closely because Renagel may decrease the levels of bicarbonate. Special note for patients on peritoneal dialysis You may develop peritonitis (infection of your abdominal fluid) associated with your peritoneal dialysis. This risk can be reduced by careful adherence to sterile techniques during bag changes. You should tell your doctor immediately if you experience any new signs or symptoms of abdominal distress, abdominal swelling, abdominal pain, abdominal tenderness, or abdominal rigidity, constipation, fever, chills, nausea or vomiting. You should expect to be monitored more carefully for problems with low levels of vitamins A, D, E, K and folic acid. Children and adolescents The safety and efficacy in children (below the age of 18 years) has not been studied. Therefore Renagel is not recommended for use in this population. Other medicines and Renagel Tell your doctor if you are taking, have recently taken or might take any other medicines.

• Renagel should not be taken at the same time as ciprofloxacin (an antibiotic).

• If you are taking medicines for heart rhythm problems or for epilepsy, you should consult your doctor when taking Renagel.

• The effects of medicines such as ciclosporin, mycophenolate mofetil and tacrolimus

(medicines used in transplant patients) may be reduced by Renagel. Your doctor will advise you if you are taking these medicines.

• In certain people taking levothyroxine (a thyroid hormone) and Renagel, increased levels of

thyroid stimulating hormone (TSH, a substance in your blood which helps control your body’s chemical functions) may very rarely be observed. Therefore your doctor may monitor the levels of TSH in your blood more closely.

• If you are taking medicine such as omeprazole, pantoprazole, or lansoprazole to treat heartburn, gastroesophageal reflux disease (GERD), or gastric ulcers, you should consult your doctor when taking Renagel.

Your doctor will check for interactions between Renagel and other medicines on a regular basis.

45

In some cases where Renagel should be taken at the same time as another medicine, your doctor may advise you to take this medicine 1 hour before or 3 hours after Renagel intake, or he/she may consider monitoring the blood levels of that medicine. Pregnancy and breast-feeding The safety of Renagel has not been established in pregnant or breast-feeding women. Renagel should only be given to pregnant or breast-feeding women if clearly needed. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Driving and using machines Renagel is unlikely to affect your ability to drive or to use machines. 3. How to take Renagel Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. He will base the dose on your serum phosphate level. The recommended starting dose of Renagel for adults and the elderly (>65 years) is two to four tablets with each meal 3 times a day. Initially your doctor will check the levels of phosphate in your blood every 2-3 weeks and may adjust the dose of Renagel when necessary (between 1 and 10 tablets of 400 mg per meal) to reach an adequate phosphate level. The tablets must be swallowed whole. Do not crush, chew or break into pieces prior to swallowing. Patients taking Renagel should adhere to their prescribed diet and liquid intake. If you take more Renagel than you should In the event of a possible overdose you should contact your doctor immediately. If you forget to take Renagel If you have missed one dose, this dose should be omitted and the next dose should be taken at the usual time with a meal. Do not take a double dose to make up for a forgotten dose. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Since constipation may be a preceding symptom in very rare cases of blockages in your intestine, it is important to inform your doctor or pharmacist of this symptom before or during the use of Renagel. The following side effects have been reported in patients taking Renagel: Very common (may affect more than 1 in 10 people): nausea, vomiting. Common (may affect up to 1 in 10 people): diarrhoea, indigestion, abdominal pain, constipation, flatulence. Uncommon (may affect up to 1 in 100 people): increased acidity of the blood. Very rare (may affect up to 1 in 10000 people): hypersensitivity. Not known (frequency cannot be estimated from the available data): cases of itching, rash, abdominal pain, slow intestine motility (movement), inflammation of abnormal small pouches (called diverticula) in the large intestine, blockages in the intestine (signs include: severe bloating; abdominal pain, swelling or cramps; severe constipation), rupture in the intestine wall

46

(signs include: severe stomach pain, chills, fever, nausea, vomiting, or a tender abdomen), intestinal bleeding, inflammation of the large bowel and crystal deposit in the intestine have been reported. Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Renagel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date stated on the carton and bottle after “EXP”. The expiry date refers to the last day of that month. Do not store this medicine above 25 °C. Keep the bottle tightly closed in order to protect from moisture. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Renagel contains - The active substance is sevelamer hydrochloride. Each tablet contains 400 mg sevelamer hydrochloride. - The other ingredients are silica colloidal anhydrous and stearic acid, hypromellose (E464), diacetylated monoglycerides, iron oxide black (E172) and propylene glycol. What Renagel looks like and contents of the pack Renagel tablets are film coated, off white, oval tablets with Renagel 400 imprinted on one side. The tablets are packed in high density polyethylene bottles with a child resistant polypropylene closure and an induction seal. Pack sizes are: 1 bottle of 360 tablets multipacks containing 720 tablets (2 bottles of 360 tablets) multipacks containing 1080 tablets (3 bottles of 360 tablets) Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Genzyme Europe B.V. Paasheuvelweg 25 1105 BP Amsterdam The Netherlands


47

Manufacturer: Genzyme Ireland Ltd IDA Industrial Park Old Kilmeaden Road Waterford Ireland Genzyme Ltd 37 Hollands Road Haverhill, Suffolk CB9 8PU United Kingdom For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien/ Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: + 32 2 710 54 00

Lietuva UAB „SANOFI-AVENTIS LIETUVA“ Tel. +370 5 275 5224

България SANOFI BULGARIA EOOD Tел: +359 2 9705300

Magyarország SANOFI-AVENTIS Zrt Tel: +36 1 505 0050

Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111

Malta Sanofi Malta Ltd Tel: +356 21493022

Danmark Sanofi A/S Tlf: +45 45 16 70 00

Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000

Deutschland Sanofi-Aventis Deutschland GmbH Tel: +49 (0)180 2 222010

Norge sanofi-aventis Norge AS Tlf: + 47 67 10 71 00

Eesti sanofi-aventis Estonia OÜ Tel. +372 6 273 488

Österreich sanofi-aventis GmbH Tel: + 43 1 80 185 - 0

Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 1600

Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00

España sanofi-aventis, S.A. Tel: +34 93 485 94 00

Portugal Sanofi – Produtos Farmacêuticos, Lda. Tel: +351 21 35 89 400

48

France sanofi-aventis France Tél : 0 800 222 555 Appel depuis l’étranger : +33 1 57 63 23 23

România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36

Hrvatska sanofi-aventis Croatia d.o.o. Tel: +385 1 600 34 00

Slovenija sanofi-aventis d.o.o. Tel: +386 1 560 4800

Ireland sanofi-aventis Ireland Ltd T/A SANOFI Tel: +353 (0) 1 4035 600

Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel.: +421 2 33 100 100

Ísland Vistor hf. Sími: +354 535 7000

Suomi/Finland Sanofi Oy Puh/Tel: + 358 201 200 300

Italia Sanofi S.p.A. Tel: 800.536 389

Sverige Sanofi AB Tel: +46 (0)8 634 50 00

Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600

United Kingdom Sanofi Tel: +44 (0) 845 372 7101

Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51

This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu

http://www.emea.europa.eu/

49

Package leaflet: Information for the user

Renagel 800 mg film-coated tablets sevelamer hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours. - If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4. What is in this leaflet 1. What Renagel is and what it is used for 2. What you need to know before you take Renagel 3. How to take Renagel 4. Possible side effects 5. How to store Renagel 6. Contents of the pack and other information. 1. What Renagel is and what it is used for Renagel contains sevelamer as the active ingredient. It binds phosphate from food in the digestive tract and so reduces serum phosphate levels in the blood. Renagel is used to control the levels of phosphate in the blood of adult kidney failure patients on haemodialysis or peritoneal dialysis treatment. Adult patients whose kidneys have failed and who are undergoing haemodialysis or peritoneal dialysis are not able to control the level of serum phosphate in their blood. The amount of phosphate then rises (your doctor will call this hyperphosphataemia). Increased levels of serum phosphorus can lead to hard deposits in your body called calcification. These deposits can stiffen your blood vessels and make it harder for blood to be pumped around the body. Increased serum phosphorus can also lead to itchy skin, red eyes, bone pain and fractures. Renagel may be used with other medicines which include calcium or vitamin D supplements to control the development of renal bone disease. 2. What you need to know before you take Renagel Do not take Renagel: • if you have low levels of phosphate in your blood (your doctor will check this for you). • if you have bowel obstruction. • if you are allergic to sevelamer or to any of the other ingredients of this medicine (listed in

section 6). Warnings and precautions Talk to your doctor before taking Renagel if any of the following applies to you:

• if you are not on dialysis • if you have swallowing problems • if you have problems with motility (movement) in your stomach and bowel • if you have symptoms of delayed emptying of stomach contents such as feeling of fullness,

nausea and/or vomiting

50

• if you have prolonged diarrhoea or pain in the abdomen (symptoms of active inflammatory bowel disease)

• if you have undergone major surgery on your stomach or bowel. • if you have serious inflammatory bowel disease.

Additional treatments: Due to either your kidney condition or your dialysis treatment you may: • develop a low or high level of calcium in your blood. Since Renagel does not contain calcium

your doctor might prescribe additional calcium tablets. • have a low amount of vitamin D in your blood. Therefore, your doctor may monitor the levels

of vitamin D in your blood and prescribe additional vitamin D as necessary. If you do not take multivitamin supplements you may also develop low levels of vitamins A, E, K and folic acid in your blood and therefore your doctor may monitor these levels and prescribe supplemental vitamins as necessary.

Changing treatment: When you switch from another phosphate binder to Renagel, your doctor might consider monitoring the levels of bicarbonate in your blood more closely because Renagel may decrease the levels of bicarbonate. Special note for patients on peritoneal dialysis: You may develop peritonitis (infection of your abdominal fluid) associated with your peritoneal dialysis. This risk can be reduced by careful adherence to sterile techniques during bag changes. You should tell your doctor immediately if you experience any new signs or symptoms of abdominal distress, abdominal swelling, abdominal pain, abdominal tenderness, or abdominal rigidity, constipation, fever, chills, nausea or vomiting. You should expect to be monitored more carefully for problems with low levels of vitamins A, D, E, K and folic acid. Children and adolescents The safety and efficacy in children (below the age of 18 years) has not been studied. Therefore Renagel is not recommended for use in this population. Other medicines and Renagel Tell your doctor if you are taking, have recently taken or might take any other medicines.

• Renagel should not be taken at the same time as ciprofloxacin (an antibiotic).

• If you are taking medicines for heart rhythm problems or for epilepsy, you should consult your doctor when taking Renagel.

• The effects of medicines such as ciclosporin, mycophenolate mofetil and tacrolimus

(medicines used in transplant patients) may be reduced by Renagel. Your doctor will advise you if you are taking these medicines.

• In certain people taking levothyroxine (a thyroid hormone) and Renagel, increased levels of

thyroid stimulating hormone (TSH, a substance in your blood which helps control your body’s chemical functions) may very rarely be observed. Therefore your doctor may monitor the levels of TSH in your blood more closely.

• If you are taking medicine such as omeprazole, pantoprazole, or lansoprazole to treat heartburn,

gastroesophageal reflux disease (GERD), or gastric ulcers, you should consult your doctor when taking Renagel. Your doctor will check for interactions between Renagel and other medicines on a regular basis.

51

In some cases where Renagel should be taken at the same time as another medicine, your doctor may advise you to take this medicine 1 hour before or 3 hours after Renagel intake, or he/she may consider monitoring the blood levels of that medicine. Pregnancy and breast-feeding The safety of Renagel has not been established in pregnant or breast-feeding women. Renagel should only be given to pregnant or breast-feeding women if clearly needed. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Driving and using machines Renagel is unlikely to affect your ability to drive or to use machines. 3. How to take Renagel Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. He will base the dose on your serum phosphate level. The recommended starting dose of Renagel for adults and the elderly (>65 years) is one or two tablets with each meal 3 times a day. Initially your doctor will check the levels of phosphate in your blood every 2-3 weeks and may adjust the dose of Renagel when necessary (between 1 and 5 tablets of 800 mg per meal) to reach an adequate phosphate level. The tablets must be swallowed whole. Do not crush, chew or break into pieces prior to swallowing. Patients taking Renagel should adhere to their prescribed diet and liquid intake. If you take more Renagel than you should In the event of a possible overdose you should contact your doctor immediately. If you forget to take Renagel If you have missed one dose, this dose should be omitted and the next dose should be taken at the usual time with a meal. Do not take a double dose to make up for a forgotten dose. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Since constipation may be a preceding symptom in very rare cases of blockages in your intestine, it is important to inform your doctor or pharmacist of this symptom before or during the use of Renagel. The following side effects have been reported in patients taking Renagel: Very common (may affect more than 1 in 10 people): nausea, vomiting. Common (may affect up to 1 in 10 people): diarrhoea, indigestion, abdominal pain, constipation, flatulence. Uncommon (may affect up to 1 in 100 people): increased acidity of the blood. Very rare (may affect up to 1 in 10000 people): hypersensitivity. Not known (frequency cannot be estimated from the available data): cases of itching, rash, abdominal pain, slow intestine motility (movement), , inflammation of abnormal small pouches (called diverticula) in the large intestine, blockages in the intestine (signs include:

52

severe bloating; abdominal pain, swelling or cramps; severe constipation), rupture in the intestine wall (signs include: severe stomach pain, chills, fever, nausea, vomiting, or a tender abdomen), intestinal bleeding, inflammation of the large boweland crystal deposit in the intestine have been reported. Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Renagel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date stated on the carton and bottle after “EXP”. The expiry date refers to the last day of that month. Do not store this medicine above 25 °C. Keep the bottle tightly closed in order to protect from moisture. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Renagel contains - The active substance is sevelamer hydrochloride. Each tablet contains 800 mg sevelamer hydrochloride. - The other ingredients are silica colloidal anhydrous and stearic acid, hypromellose (E464), diacetylated monoglycerides, iron oxide black (E172) and propylene glycol. What Renagel looks like and contents of the pack Renagel tablets are film coated, off white, oval tablets with Renagel 800 imprinted on one side. The tablets are packed in high density polyethylene bottles with a child resistant polypropylene closure and an induction seal. Pack sizes are: 1 bottle of 100 tablets 1 bottle of 180 tablets multipacks containing 180 tablets (6 bottles of 30 tablets) multipacks containing 360 tablets (2 bottles of 180 tablets) multipacks containing 540 tablets (3 bottles of 180 tablets) Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Genzyme Europe B.V. Paasheuvelweg 25 1105 BP Amsterdam The Netherlands


53

Manufacturer: Genzyme Ireland Ltd IDA Industrial Park Old Kilmeaden Road Waterford Ireland Genzyme Ltd 37 Hollands Road Haverhill, Suffolk CB9 8PU United Kingdom For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien/ Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: + 32 2 710 54 00

Lietuva UAB „SANOFI-AVENTIS LIETUVA“ Tel. +370 5 275 5224

България SANOFI BULGARIA EOOD Tел: +359 2 9705300

Magyarország SANOFI-AVENTIS Zrt Tel: +36 1 505 0050

Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111

Malta Sanofi Malta Ltd Tel: +356 21493022

Danmark Sanofi A/S Tlf: +45 45 16 70 00

Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000

Deutschland Sanofi-Aventis Deutschland GmbH Tel: +49 (0)180 2 222010

Norge sanofi-aventis Norge AS Tlf: + 47 67 10 71 00

Eesti sanofi-aventis Estonia OÜ Tel. +372 6 273 488

Österreich sanofi-aventis GmbH Tel: + 43 1 80 185 - 0

Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 1600

Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00

España sanofi-aventis, S.A. Tel: +34 93 485 94 00

Portugal Sanofi – Produtos Farmacêuticos, Lda. Tel: +351 21 35 89 400

France sanofi-aventis France Tél : 0 800 222 555 Appel depuis l’étranger : +33 1 57 63 23 23

România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36

Hrvatska sanofi-aventis Croatia d.o.o.

Slovenija sanofi-aventis d.o.o.

54

Tel: +385 1 600 34 00

Tel: +386 1 560 4800

Ireland sanofi-aventis Ireland Ltd T/A SANOFI Tel: +353 (0) 1 4035 600

Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel.: +421 2 33 100 100

Ísland Vistor hf. Sími: +354 535 7000

Suomi/Finland Sanofi Oy Puh/Tel: + 358 201 200 300

Italia Sanofi S.p.A. Tel: 800.536 389

Sverige Sanofi AB Tel: +46 (0)8 634 50 00

Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600

United Kingdom Sanofi Tel: +44 (0) 845 372 7101

Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51

This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.


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Annex IV

Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

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Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for sevelamer, the scientific conclusions of CHMP are as follows:

During the period covered by this PSUR 14 case reports of gastrointestinal (GI) disorders associated with sevelamer crystals have been published, including one case of colonic/caecal mass formation.

Considering the seriousness of these events, the increasing number of well-documented and published reported cases, including the 4 cases with a positive dechallenge after discontinuation of sevelamer only, the risk of “sevelamer crystals associated with serious gastrointestinal disorders” should be updated in section 4.4 and should also be reflected in section 4.8 of the SmPC and in the corresponding sections of the package leaflet.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for sevelamer the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing sevelamer is unchanged subject to the proposed changes to the product information

The CHMP recommends that the terms of the marketing authorisation(s) should be varied.

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS · Intestinal obstruction and ileus/subileus In very...

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